ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Uptravi 100 microgram film-coated tablets

Uptravi 200 microgram film-coated tablets

Uptravi 400 microgram film-coated tablets

Uptravi 600 microgram film-coated tablets

Uptravi 800 microgram film-coated tablets

Uptravi 1 000 microgram film-coated tablets

Uptravi 1 200 microgram film-coated tablets

Uptravi 1 400 microgram film-coated tablets

Uptravi 1 600 microgram film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Uptravi 100 microgram film-coated tablets

Each film-coated tablet contains 100 micrograms of selexipag.

Uptravi 200 microgram film-coated tablets

Each film-coated tablet contains 200 micrograms of selexipag.

Uptravi 400 microgram film-coated tablets

Each film-coated tablet contains 400 micrograms of selexipag.

Uptravi 600 microgram film-coated tablets

Each film-coated tablet contains 600 micrograms of selexipag.

Uptravi 800 microgram film-coated tablets

Each film-coated tablet contains 800 micrograms of selexipag.

Uptravi 1 000 microgram film-coated tablets

Each film-coated tablet contains 1 000 micrograms of selexipag.

Uptravi 1 200 microgram film-coated tablets

Each film-coated tablet contains 1 200 micrograms of selexipag.

Uptravi 1 400 microgram film-coated tablets

Each film-coated tablet contains 1 400 micrograms of selexipag.

Uptravi 1 600 microgram film-coated tablets

Each film-coated tablet contains 1 600 micrograms of selexipag.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Uptravi 100 microgram film-coated tablets

Round, 3.0 mm diameter, light-yellow, film-coated tablets, with “1” debossed on one side.

Uptravi 200 microgram film-coated tablets

Round, 7.3 mm diameter, light-yellow, film-coated tablets,with “2” debossed on one side.

Uptravi 400 microgram film-coated tablets

Round, 7.3 mm diameter, red, film-coated tablets with “4” debossed on one side.

Uptravi 600 microgram film-coated tablets

Round, 7.3 mm diameter, light-violet, film-coated tablets with “6” debossed on one side.

Uptravi 800 microgram film-coated tablets

Round, 7.3 mm diameter, green, film-coated tablets with “8” debossed on one side.

Uptravi 1 000 microgram film-coated tablets

Round, 7.3 mm diameter, orange, film-coated tablets with “10” debossed on one side.

Uptravi 1 200 microgram film-coated tablets

Round, 7.3 mm diameter, dark-violet, film-coated tablets with “12” debossed on one side.

Uptravi 1 400 microgram film-coated tablets

Round, 7.3 mm diameter, dark-yellow, film-coated tablets with “14” debossed on one side.

Uptravi 1 600 microgram film-coated tablets

Round, 7.3 mm diameter, brown, film-coated tablets with “16” debossed on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult

patients with WHO functional class (FC) II–III, either as combination therapy in patients insufficiently

controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5)

inhibitor, or as monotherapy in patients who are not candidates for these therapies.

Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH

associated with connective tissue disorders, and PAH associated with corrected simple congenital

heart disease (see section 5.1).

4.2 Posology and method of administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Posology

Individualised dose titration

Each patient should be up-titrated to the highest individually tolerated dose, which can range from

200 micrograms given twice daily to 1 600 micrograms given twice daily (individualised maintenance

dose).

The recommended starting dose is 200 micrograms given twice daily, approximately 12 hours apart.

The dose is increased in increments of 200 micrograms given twice daily, usually at weekly intervals.

At the beginning of treatment and at each up-titration step it is recommended to take the first dose in

the evening. During dose titration some adverse reactions, reflecting the mode of action of selexipag

(such as headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia,

and flushing), may occur. They are usually transient or manageable with symptomatic treatment (see

section 4.8). However, if a patient reaches a dose that cannot be tolerated, the dose should be reduced

to the previous dose level.

In patients in whom up-titration was limited by reasons other than adverse reactions reflecting the

mode of action of selexipag, a second attempt to continue up-titration to the highest individually

tolerated dose up to a maximum dose of 1 600 micrograms twice daily may be considered.

Individualised maintenance dose

The highest tolerated dose reached during dose titration should be maintained. If the therapy over time

is less tolerated at a given dose, symptomatic treatment and/or a dose reduction to the next lower dose

should be considered.

Interruptions and discontinuations

If a dose is missed, it should be taken as soon as possible. The missed dose should not be taken if the

next scheduled dose is within approximately 6 hours.

If treatment is missed for 3 days or more, Uptravi should be restarted at a lower dose and then

up-titrated.

There is limited experience with abrupt discontinuation of selexipag in patients with PAH. No

evidence for acute rebound has been observed.

However, if the decision to withdraw Uptravi is taken, it should be done gradually while an alternative

therapy is introduced.

Dose adjustment with co-administration of moderate CYP2C8 inhibitors

When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and

teriflunomide), the total daily dose of Uptravi should be reduced to half by administering half of each

dose twice daily.Alternatively, a once daily dosing frequency to achieve half of the daily dose of

Uptravi may be continued in patients already well controlled on a once daily dosing regimen or may

be applied in patients for whom the appropriate dose strength(s) supporting twice daily dosing with

half the dose is not available. If the therapy is not tolerated at a given dose, symptomatic treatment

and/or a dose reduction to the next lower dose should be considered. When co-administration of a

moderate CYP2C8 inhibitor is stopped,the total daily dose of Uptravi should be increased,as

applicable. The maximum dose of 1 600 micrograms twice daily should not be exceeded (see

section 4.5).

Special populations

Elderly (≥ 65 years)

No adjustment to the dose regimen is needed in elderly people (see section 5.2). There is limited

clinical experience in patients over the age of 75 years, therefore Uptravi should be used with caution

in this population (see section 4.4).

Hepatic impairment

Uptravi should not be administered in patients with severe liver impairment (Child-Pugh class C; see

section 4.4). For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of

treatment should be 100 micrograms twice daily and increased at weekly intervals by increments of

100 micrograms twice daily until adverse reactions, reflecting the mode of action of selexipag, that

cannot be tolerated or medically managed are experienced. In these patients the maximum dose is

800 micrograms given twice daily. Alternatively, a once daily dosing frequency to achieve half of the

daily dose of Uptravi may be continued in patients already well controlled on a once daily dosing

regimen or may be applied in patients for whom the appropriate dose strength(s) supporting twice

daily dosing with half the dose is not available.No adjustment to the dose regimen is needed in

patients with mild hepatic impairment (Child-Pugh class A).

Renal impairment

No adjustment to the dose regimen is needed in patients with mild or moderate renal impairment. No

change in starting dose is required in patients with severe renal impairment (estimated glomerular

filtration rate [eGFR] < 30 mL/min/1.73 m2); dose titration should be done with caution in these

patients (see section 4.4).

Paediatric population

The safety and efficacy of selexipag in children aged 2 to less than 18 years have not yet been

established. Currently available interim data are described in sections 5.1 and 5.2, but no

recommendation on a posology can be made. Administration of selexipag in the paediatric population

is not recommended.

The safety and efficacy of selexipag in children aged less than 2 years have not been studied, as

animal studies indicated an increased risk of intussusception. The clinical relevance of these findings

is unknown (see section 5.3).

Method of administration

Oral use.

The film-coated tablets are to be taken orally in the morning and in the evening. To improve

tolerability, it is recommended to take Uptravi with food and, at the beginning of each up-titration

phase, to take the first increased dose in the evening.

The film-coated tablets are to be swallowed with water. The tablets should not be split or crushed

because the tablet coating protects the active substance from light.

Patients who have poor vision or are blind must be instructed to get assistance from another person

when taking Uptravi during the titration period.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe coronary heart disease or unstable angina.

Myocardial infarction within the last 6 months.

Decompensated cardiac failure if not under close medical supervision.

Severe arrhythmias.

Cerebrovascular events (e.g., transient ischaemic attack, stroke) within the last 3 months.

Congenital or acquired valvular defects with clinically relevant myocardial function disorders

not related to pulmonary hypertension.

Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil; see section 4.5).

4.4 Special warnings and precautions for use

Hypotension

Selexipag has vasodilatory properties that may result in lowering of blood pressure. Before prescribing

Uptravi, physicians should carefully consider whether patients with certain underlying conditions

could be adversely affected by vasodilatory effects (e.g., patients on antihypertensive therapy or with

resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or autonomic

dysfunction) (see section 4.8).

Hyperthyroidism

Hyperthyroidism has been observed with Uptravi. Thyroid function tests are recommended as

clinically indicated in the presence of signs or symptoms of hyperthyroidism (see section 4.8).

Pulmonary veno-occlusive disease

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in

patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur

when Uptravi is administered in patients with PAH, the possibility of pulmonary veno-occlusive

disease should be considered. If confirmed, treatment is to be discontinued.

Elderly (≥ 65 years)

There is limited clinical experience with selexipag in patients over the age of 75 years, therefore,

Uptravi should be used with caution in this population (see section 4.2).

Hepatic impairment

There is no clinical experience with selexipag in patients with severe liver impairment (Child-Pugh

class C), therefore treatment should not be administered in these patients. The exposure to selexipag

and its active metabolite is increased in subjects with moderate hepatic impairment (Child-Pugh

class B; see section 5.2). In patients with moderate hepatic impairment, the total daily dose of Uptravi

should be reduced (see section 4.2).

Renal impairment

In patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), caution should be exercised

during dose titration. There is no experience with Uptravi in patients undergoing dialysis (see

section 5.2), therefore Uptravi should not be used in these patients.

Women of childbearing potential

Women of childbearing potential should practise effective contraception while taking selexipag (see

section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on selexipag

Selexipag is hydrolysed to its active metabolite by carboxylesterases (see section 5.2). Selexipag and

its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by

CYP3A4. The glucuronidation of the active metabolite is catalysed by UGT1A3 and UGT2B7.

Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a weak

substrate of the P-gp efflux pump. The active metabolite is a weak substrate of the breast cancer

resistance protein (BCRP).

The pharmacokinetics of selexipag and its active metabolite are not affected by warfarin.

Inhibitors of CYP2C8

In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of CYP2C8, exposure to

selexipag increased approximately 2-fold, whereas exposure to the active metabolite, the major

contributor to efficacy, increased approximately 11-fold. Concomitant administration of Uptravi with

strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated (see section 4.3).

Concomitant administration of Uptravi with clopidogrel (loading dose of 300 mg or maintenance dose

of 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to

selexipag but increased the exposure to the active metabolite approximately 2.2 and 2.7-fold following

loading dose and maintenance dose, respectively. The total daily dose of Uptravi should be decreased

by reducing each dose to half when co-administered with moderate CYP2C8 inhibitors (e.g.,

clopidogrel, deferasirox, teriflunomide). Alternatively, a once daily dosing frequency to achieve half

of the daily dose of Uptravi may be continued in patients already well controlled on a once daily

dosing regimen or may be applied in patients for whom the appropriate dose strength(s) supporting

twice daily dosing with half the dose is not available.When co-administration of a moderate CYP2C8

inhibitor is stopped increase the total daily dose of Uptravi, as applicable. The maximum dose of 1 600

micrograms twice daily should not be exceeded (see section 4.2).

Inducers of CYP2C8

In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 (and UGT enzymes), the

exposure to selexipag did not change, whereas exposure to the active metabolite was reduced by half.

Dose adjustment of selexipag may be required with concomitant administration of inducers of

CYP2C8 (e.g., rifampicin, carbamazepine, phenytoin).

Inhibitors of UGT1A3 and UGT2B7

The effect of strong inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole)

on the exposure to selexipag and its active metabolite has not been studied. Caution is required when

administering these medicinal products concomitantly with Uptravi. A potential pharmacokinetic

interaction with strong inhibitors of UGT1A3 and UGT2B7 cannot be excluded.

Inhibitors and inducers of CYP3A4

In the presence of 400 mg/100 mg lopinavir/ritonavir twice daily, a strong CYP3A4 inhibitor,

exposure to selexipag increased approximately 2-fold, whereas the exposure to the active metabolite of

selexipag did not change. Given the 37-fold higher potency of the active metabolite, this effect is not

clinically relevant. Since a strong inhibitor of CYP3A4 did not affect the pharmacokinetics of the

active metabolite, indicating that the CYP3A4 pathway is not important in the elimination of the active

metabolite, no effect of inducers of CYP3A4 on the pharmacokinetics of the active metabolite is

expected.

PAH-specific therapies

In the phase 3 placebo-controlled trial in patients with PAH, the use of selexipag in combination with

both an ERA and a PDE-5 inhibitor resulted in a 30% lower exposure to the active metabolite.

Transporter inhibitors (lopinavir/ritonavir)

In the presence of 400 mg/100 mg lopinavir/ritonavir twice daily, a strong OATP (OATP1B1 and

OATP1B3) and P-gp inhibitor, exposure to selexipag increased approximately 2-fold, whereas the

exposure to the active metabolite of selexipag did not change. Given that the majority of the

pharmacological effect is driven by the active metabolite, this effect is not clinically relevant.

Effect of selexipag on other medicinal products

Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes and transport

proteins at clinically relevant concentrations.

Anticoagulants or inhibitors of platelet aggregation

Selexipag is an inhibitor of platelet aggregation in vitro. In the phase 3 placebo-controlled study in

patients with PAH, no increased risk of bleeding was detected with selexipag compared to placebo,

including when selexipag was administered with anticoagulants (such as heparin, coumarin-type

anticoagulants) or inhibitors of platelet aggregation. In a study in healthy subjects, selexipag

(400 micrograms twice daily) did not alter the exposure to S-warfarin (CYP2C9 substrate) or

R-warfarin (CYP3A4 substrate) after a single dose of 20 mg warfarin. Selexipag did not influence the

pharmacodynamic effect of warfarin on the international normalised ratio.

Midazolam

At steady state after up-titration to 1 600 micrograms selexipag twice a day, no clinically relevant

change in exposure to midazolam, a sensitive intestinal and hepatic CYP3A4 substrate, or its

metabolite, 1-hydroxymidazolam, was observed. Concomitant administration of selexipag with

CYP3A4 substrates does not require dose adjustment.

Hormonal contraceptives

Specific drug-drug interaction studies with hormonal contraceptives have not been conducted. Since

selexipag did not affect the exposure to the CYP3A4 substrates midazolam and R-warfarin or to the

CYP2C9 substrate S-warfarin, reduced efficacy of hormonal contraceptives is not expected.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should practise effective contraception while taking selexipag (see

section 4.4).

Pregnancy

There are no data from the use of selexipag in pregnant women. Animal studies do not indicate direct

or indirect harmful effects with respect to reproductive toxicity. Selexipag and its main metabolite

showed 20-to 80-times lower prostacyclin (IP) receptor potency in vitro for animal species used in

reproductive toxicity testing compared to humans. Therefore, safety margins for potential

IP receptor-mediated effects on reproduction are accordingly lower than for non-IP-related effects (see

section 5.3).

Uptravi is not recommended during pregnancy and in women of childbearing potential not using

contraception.

Breast-feeding

It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or its

metabolites are excreted in milk (see section 5.3). A risk to the suckling child cannot be excluded.

Uptravi should not be used during breast-feeding.

Fertility

There are no clinical data available. In rat studies, selexipag at high doses caused transient

disturbances in oestrus cycles that did not affect fertility (see section 5.3). The relevance for humans is

not known.

4.7 Effects on ability to drive and use machines

Uptravi has minor influence on the ability to drive and use machines. The clinical status of the patient

and the adverse reaction profile of selexipag (such as headache or hypotension, see section 4.8) should

be kept in mind when considering the patient’s ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are headache, diarrhoea, nausea and vomiting, jaw

pain, myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during the

up-titration phase. The majority of these reactions are of mild to moderate intensity.

The safety of selexipag has been evaluated in a long-term, phase 3 placebo-controlled study enrolling

1 156 adult patients with symptomatic PAH (GRIPHON study). The mean treatment duration was

76.4 weeks (median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median

63.7 weeks) for patients on placebo. The exposure to selexipag was up to 4.2 years.

Tabulated list of adverse reactions

Adverse reactions obtained from the pivotal clinical GRIPHON study and post-marketing surveillance

are tabulated below. The adverse reactions are ranked by frequency within each system organ class

(SOC) and presented in order of decreasing seriousness. Frequencies are defined as very common

(≥ 1/10), common (≥1/100 to <1/10); uncommon (≥1/1 000 to < 1/100); rare (≥1/10 000 to

<1/1 000); very rare (< 1/10 000).

System organ class Very common Common Uncommon

Blood and lymphatic

disorders

Anaemia*

Haemoglobin decreased

Endocrine disorders Hyperthyroidism*

Thyroid-stimulating

Hormone decreased

Metabolism and

nutrition disorders

Decreased appetite

Weight decrease

Nervous system

disorders

Headache*

Cardiac disorders

Sinus tachycardia

Vascular disorders

Flushing*

Hypotension

Respiratory, thoracic

and mediastinal

disorders

Nasopharyngitis (of

non-infectious

origin)

Nasal congestion

Gastro-intestinal

disorders

Diarrhoea*

Vomiting*

Nausea*

Abdominal pain

Dyspepsia*

Skin and subcutaneous

tissue disorders

Rash

Urticaria

Erythema

Angioedema

†

Musculoskeletal and

connective tissue

disorders

Jaw pain*

Myalgia*

Arthralgia*

Pain in extremity*

General disorders and

administration site

conditions

Pain

See section Description of selected adverse reactions.

†Cases of angioedema have been reported in post-marketing experience with a latency that can exceed 30 days of treatment.

Description of selected adverse reactions

Pharmacological effects associated with titration and maintenance treatment

Adverse reactions associated with the mode of action of selexipag have been observed frequently, in

particular during the phase of individualised dose titration, and are tabulated below:

Prostacyclin-like associated

adverse reactions

Titration Maintenance

Selexipag Placebo Selexipag Placebo

Headache

64%

28%

40%

20%

Diarrhoea

36%

12%

30%

13%

Nausea

29%

13%

20%

10%

Pain in jaw

26%

21%

Myalgia

15%

Pain in extremity

14%

13%

Vomiting

14%

Flushing

11%

10%

Arthralgia

These effects are usually transient or manageable with symptomatic treatment. 7.5% of patients on

selexipag discontinued treatment due to these adverse reactions. The approximate rate of adverse

reactions that were serious was 2.3% in the selexipag group and 0.5% in the placebo group. In clinical

practice, gastro-intestinal events have been observed to respond to anti-diarrhoeal, anti-emetic, and

anti-nauseant medicinal products and/or medicinal products for functional gastro-intestinal disorders.

Pain-associated events have frequently been treated with analgesics (such as paracetamol).

Haemoglobin decrease

In a phase 3 placebo-controlled study in patients with PAH, mean absolute changes in haemoglobin at

regular visits compared to baseline ranged from 0.34 to 0.02 g/dL in the selexipag group compared

to 0.05 to 0.25 g/dL in the placebo group. A decrease from baseline in haemoglobin concentration to

below 10 g/dL was reported in 8.6% of selexipag-treated patients and 5.0% of placebo-treated

patients.

In a phase 3 placebo-controlled study in patients newly diagnosed with PAH, mean absolute changes

in haemoglobin at regular visits compared to baseline ranged from 1.77 to 1.26 g/dL in the triple

therapy group (selexipag, macitentan, tadalafil) compared to 1.61 to 1.28 g/dL in the double therapy

group (placebo, macitentan and tadalafil). A decrease from baseline in haemoglobin concentration to

below 10 g/dL was reported in 19.0% of patients in the triple therapy group and 14.5% in the double

therapy group. Anaemia was reported with very common frequency (13.4%) in the triple therapy

group compared to common frequency (8.3%) in the double therapy group.

Thyroid function tests

In a phase 3 placebo-controlled study in patients with PAH, hyperthyroidism was reported for 1.6% of

patients in the selexipag group, compared to no case in the placebo group (see section 4.4). A

reduction (up to 0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating

hormone was observed at most visits in the selexipag group. In the placebo group, little change in

median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either

group.

Increase in heart rate

In the phase 3 placebo-controlled study in patients with PAH, a transient increase in mean heart rate of

3–4 bpm at 2–4 hours post-dose was observed. Electrocardiogram investigations showed sinus

tachycardia in 11.3% of patients in the selexipag group compared to 8.8% in the placebo group (see

section 5.1).

Hypotension

In the phase 3 placebo-controlled study in patients with PAH, hypotension was reported for 5.8% of

patients in the selexipag group compared to 3.8% in the placebo group. Mean absolute changes in

systolic blood pressure at regular visits compared to baseline ranged from 2.0 to 1.5 mmHg in the

selexipag group compared to 1.3 to 0.0 mmHg in the placebo group and in diastolic blood pressure

ranged from 1.6 to 0.1 mmHg in the selexipag group compared to 1.1 to 0.3 mmHg in the placebo

group. Systolic blood pressure decrease below 90 mmHg was recorded for 9.7% of patients in the

selexipag group compared 6.7% in the placebo group.

Dyspepsia

In a phase 3 placebo-controlled study in patients newly diagnosed with PAH, dyspepsia was reported

with very common frequency (16.8%) in patients receiving triple therapy (selexipag, macitentan,

tadalafil) compared to common frequency (8.3%) in patients receiving double therapy (placebo,

macitentan and tadalafil).

Long-term safety

Of the 1 156 patients who participated in the pivotal study,709 patients entered a long-term open-label

extension study (330 patients who continued on selexipag from the GRIPHON study and 379 patients

who received placebo in GRIPHON and crossed over to selexipag). Long-term follow up of patients

treated with selexipag for a median treatment duration of 30.5 months and for a maximum of up to

103 months showed a safety profile that was similar to that observed in the pivotal clinical study

described above.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9 Overdose

Isolated cases of overdose up to 3 200 micrograms were reported in adults. Mild, transient nausea was

the only reported consequence. In the event of overdose, supportive measures must be taken as

required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly

protein bound.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin,

ATC code: B01AC27

Mechanism of action

Selexipag is a selective IP receptor agonist distinct from prostacyclin and its analogues. Selexipag is

hydrolysed by carboxylesterases to yield its active metabolite, which is approximately 37-fold more

potent than selexipag. Selexipag and the active metabolite are high-affinity IP receptor agonists with a

high selectivity for the IP receptor versus other prostanoid receptors (EP1–EP4, DP, FP, and TP).

Selectivity against EP1, EP3, FP, and TP is important because these are well-described contractile

receptors in the gastro-intestinal tract and blood vessels. Selectivity against EP2, EP4, and DP1is

important because these receptors mediate immune depressive effects.

Stimulation of the IP receptor by selexipag and the active metabolite leads to vasodilatory as well as

anti-proliferative and anti-fibrotic effects. Selexipag prevents cardiac and pulmonary remodelling in a

rat model of PAH and causes proportional decreases in pulmonary and peripheral pressures, indicating

that peripheral vasodilation reflects pulmonary pharmacodynamic efficacy. Selexipag does not cause

IP receptor desensitisation in vitro nor tachyphylaxis in a rat model.

Pharmacodynamic effects

Cardiac electrophysiology

In a thorough QT study in healthy adult subjects, repeated doses of 800 and 1 600 micrograms of

selexipag twice daily did not show an effect on cardiac repolarisation (QTcinterval) or conduction (PR

and QRS intervals) and had a mild accelerating effect on heart rate (the placebo-corrected,

baseline-adjusted increase in heart rate reached 6–7 bpm at 1.5 to 3 h after dosing with

800 micrograms selexipag and 9-10 bpm at the same timepoints after 1 600 micrograms selexipag).

Coagulation factors

In phase 1 and 2 studies a slight decrease in plasma levels of von Willebrand factor (vWF) was

observed with selexipag; the vWF values remained above the lower limit of the normal range.

Pulmonary haemodynamics

A phase 2 double-blind, placebo-controlled clinical study assessed haemodynamic variables after

17 weeks of treatment in adult patients with PAH WHO FC II–III and concomitantly receiving ERAs

and/or PDE-5 inhibitors. Patients titrating selexipag to an individually tolerated dose (200 micrograms

twice daily increments up to 800 micrograms twice daily; N =33) achieved a statistically significant

mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI]: 44.7%,

12.2%; p =0.0045) and an increase in cardiac index (mean treatment effect) of 0.48 L/min/m2(95%

CI: 0.13, 0.83) compared to placebo (N =10).

Clinical efficacy and safety

Efficacy in adult patients with PAH (GRIPHON)

The effect of selexipag on progression of PAH was demonstrated in a multi-centre, long-term

(maximum duration of exposure approximately 4.2 years), double-blind, placebo-controlled,

parallel-group, event-driven phase 3 study (GRIPHON) in 1 156 patients with symptomatic (WHO FC

I–IV) PAH. Patients were randomised to either placebo (N =582) or selexipag (N =574) twice daily.

The dose was increased at weekly intervals by increments of 200 micrograms given twice daily to

determine the individualised maintenance dose (200–1 600 micrograms twice daily).

The primary study endpoint was the time to first occurrence of a morbidity or mortality event up to

end of treatment, defined as a composite of death (all causes); or hospitalisation for PAH; or

progression of PAH resulting in need for lung transplantation or balloon atrial septostomy; or initiation

of parenteral prostanoid therapy or chronic oxygen therapy; or other disease-progression events

(patients in WHO FC II or III at baseline) confirmed by a decrease in 6-minute walk distance

(6MWD) from baseline (≥15%) and worsening of WHO FC or (patients in WHO FC III or IV at

baseline) confirmed by a decrease in 6MWD from baseline (≥15%) and need for additional

PAH-specific therapy.

All events were confirmed by an independent adjudication committee, blinded to treatment allocation.

The mean age was 48.1 years (range 18–80 years of age), with the majority of subjects being

Caucasian (65.0%) and female (79.8%). 17.9% of patients were ≥65 and 1.1% ≥75 years of age.

Approximately 1%, 46%, 53%, and 1% of patients were in WHO FC I, II, III and IV, respectively, at

baseline.

Idiopathic or heritable PAH was the most common aetiology in the study population (58%) followed

by PAH due to connective tissue disorders (29%), PAH associated with simple corrected congenital

heart disease (10%), and PAH associated with other aetiologies (drugs and toxins [2%] and HIV

[1%]).

At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of a specific

therapy for PAH, either an ERA (15%) or a PDE-5 inhibitor (32%) or both an ERA and a PDE-5

inhibitor (33%).

The overall median double-blind treatment duration was 63.7 weeks for the placebo group and

70.7 weeks for the selexipag group. 23% of patients on selexipag achieved maintenance doses in the

range of 200–400 micrograms, 31% achieved doses in the range of 600–1 000 micrograms, and 43%

achieved doses in the range of 1 200–1 600 micrograms.

Treatment with selexipag 200–1 600 micrograms twice daily resulted in a 40% reduction (hazard ratio

[HR] 0.60; 99% CI: 0.46, 0.78; one-sided log-rank p value < 0.0001) of the occurrence of morbidity or

mortality events up to 7 days after last dose compared to placebo (Figure 1). The beneficial effect of

selexipag was primarily attributable to a reduction in hospitalisation for PAH and a reduction in other

disease-progression events (Table 1).

Figure 1Kaplan-Meier estimates of the first morbidity-mortality event

Table 1 Summary of outcome events

Endpoints &

statistics

Patients with an

event Treatment comparison: selexipag vs placebo

Placebo

(N=582)

Selexipag

(N=574)

Absolute

risk

reduction

Relative risk

reduction

(99% CI)

(99% CI) p-value

Morbidity-

mortality eventa58.3% 41.8% 16.5% 40%

(22%; 54%)

0.60

(0.46; 0.78) < 0.0001

Hospitalisation

due to PAHb

n (%)

109

(18.7%)

(13.6%) 5.1% 33%

(2%; 54%)

0.67

(0.46; 0.98) 0.04

Disease

progressionb

n (%)

100

(17.2%)

(6.6%) 10.6% 64%

(41%; 78%)

0.36

(0.22; 0.59) < 0.0001

i.v./s.c.

Prostanoid

initiation or

oxygen therapyb,c

n (%)

(2.6%)

(1.9%) 0.7% 32%

(90%; 76%)

0.68

(0.24; 1.90) 0.53

Death up to EOT

+ 7 daysd

n (%)

(6.4%)

(8.0%) 1.7% 17%

(107%; 34%)

1.17

(0.66; 2.07) 0.77

Death up to study

closured

n (%)

105

(18.0%)

100

(17.4%) 0.6% 3%

(39%; 32%)

0.97

(0.68; 1.39) 0.42

CI = confidence interval; EOT = end of treatment; HR = hazard ratio; i.v. = intravenous; PAH = pulmonary arterial

hypertension; s.c. =subcutaneous.

a% of patients with an event at 36 months = 100 × (1 –Kaplan-Meier estimate); hazard ratio estimated using Cox’s

proportional hazard model; unstratified one-sided log-rank p-value

b% of patients with an event as part of the primary endpoint up to EOT + 7 days; hazard ratio estimated using Aalen

Johansen method; 2-sided p-value using Gray’s test

cIncludes ‘Need for lung transplantation or atrial septostomy’ (1 patient on selexipag and 2 on placebo)

d% of patients with an event up to EOT + 7 days or up to study closure; hazard ratio estimated using Cox’s proportional

hazard model; unstratified one-sided log-rank p-value

The numerical increase in deaths up to end of treatment + 7days but not up to study closure was

further investigated by mathematical modelling, showing that the imbalance in deaths is consistent

with the assumption of a neutral effect on PAH mortality and reduction of non-fatal events.

The observed effect of selexipag versus placebo on the primary endpoint was consistent across

individualised maintenance dose as shown by the hazard ratio for the three pre-defined categories

(0.60 for 200–400 micrograms twice daily, 0.53 for 600–1 000 micrograms twice daily, and 0.64 for

1 200–1 600 micrograms twice daily), which was consistent with the overall treatment effect (0.60).

The efficacy of selexipag on the primary endpoint was consistent across subgroups of age, sex, race,

aetiology, geographical region, WHO FC, and as monotherapy or in combination with an ERA or a

PDE-5 inhibitor or triple combination with both an ERA and a PDE-5 inhibitor.

Time to PAH-related death or hospitalisation for PAH was assessed as a secondary endpoint. The risk

of an event for this endpoint was reduced by 30% in patients receiving selexipag compared to placebo

(HR 0.70, 99% CI: 0.50, 0.98; one-sided log-rank p = 0.0031). The percentages of patients with an

event at Month 36 were 28.9% and 41.3% in the selexipag and placebo groups, respectively, with an

absolute risk reduction of 12.4%.

The number of patients who experienced, as a first event, death due to PAH or hospitalisation for PAH

up to end of treatment was 102 (17.8%) in the selexipag group and 137 (23.5%) in the placebo group.

Death due to PAH as a component of the endpoint was observed in 16 (2.8%) patients on selexipag

and 14 (2.4%) on placebo. Hospitalisation for PAH was observed in 86 (15.0%) patients on selexipag

and 123 (21.1%) patients on placebo. Selexipag reduced the risk of hospitalisation for PAH as a first

outcome event compared to placebo (HR 0.67, 99% CI: 0.46, 0.98; one-sided log-rank p =0.04).

The total number of deaths of all causes up to study closure was 100 (17.4%) for the selexipag group

and 105 (18.0%) for the placebo group (HR 0.97, 99% CI: 0.68, 1.39). The number of deaths due to

PAH up to study closure was 70 (12.2%) for the selexipag group and 83 (14.3%) for the placebo

group.

Symptomatic endpoints

Exercise capacity was evaluated as a secondary endpoint. Median 6MWD at baseline was 376 m

(range: 90–482 m) and 369 m (range: 50–515 m) in selexipag patients and placebo patients,

respectively. Treatment with selexipag resulted in a placebo-corrected median effect on 6MWD

measured at trough (i.e., approximately 12 h post-dose) of 12 m at Week 26 (99% CI: 1, 24 m;

one-sided p value =0.0027). In patients without concurrent PAH-specific therapy, the

placebo-corrected treatment effect measured at trough was 34 m (99% CI: 10, 63 m).

Quality of life was assessed in a subset of patients in the GRIPHON study using the Cambridge

Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire. There was no significant

treatment effect from baseline to Week 26.

Long-term data in PAH

Patients enrolled into the pivotal study (GRIPHON) were eligible to enter a long-term open-label

extension study. A total of 574 patients were treated with selexipag in the GRIPHON study; of these,

330 patients continued selexipag treatment in the open-label extension study. The median follow-up

duration was 4.5 years and the median exposure to selexipag was 3 years. During the follow-up, at

least one other PAH -medicinal product was added to selexipag in 28.4% of the patients. However,

most of the treatment exposure (86.3%) in all of the 574 patients was accumulated without addition of

any new PAH medicinal product.Kaplan-Meier estimates of survival of these 574patients across the

GRIPHON and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%,

respectively.Survival at 1, 2, 5, and 7 years for 273 patients of WHO FC II at baseline of the pivotal

study were 97%, 91%, 80% and 70%, respectively, and for 294 patients of WHO FC III at baseline

were 88%, 80%, 62% and 56%, respectively. Given that additional PAH treatment was initiated in a

small proportion of patients and that there was no control group in the extension study, the survival

benefit of selexipag cannot be confirmed from these data.

Initial triple combination treatment with selexipag, macitentan and tadalafil in newly diagnosed PAH

patients

In a double blind, placebo-controlled study, a total of 247 newly diagnosed PAH patients were

randomised to evaluate the treatment effect of initial triple (selexipag, macitentan and tadalafil)

(N =123) versus initial double (placebo, macitentan and tadalafil) (N =124) therapy.

The primary endpoint, change from baseline in pulmonary vascular resistance (PVR) at Week 26, did

not show a statistically significant difference between the groups, while showing animprovement

from baseline in both treatment groups (relative reduction by 54% in the initial triple therapy group vs

52% in the initial double therapy group).

Over a median follow-up of 2 years, 4 (3.4%) patients in the triple therapy group and 12 (9.4%)

patients in the double therapy group died.

Paediatric population

Interim efficacy and safety in paediatric patients with PAH (SALTO)

The efficacy and safety in paediatric patients aged ≥ 2 to < 18 years with PAH was evaluated in a

descriptive manner in a multi-centre, randomised, double-blind, placebo-controlled, parallel-group,

phase 3 study (SALTO). A total of 138 patients were randomised 1:1 to receive either selexipag

(N =69) or placebo (N =69) twice daily. Selexipag doses of 100, 150 or 200 micrograms were

up-titrated to 800, 1 200 or 1 600 micrograms twice daily based on the weight category and tolerability

(see section 5.2). The interim analysis was performed when 92 patients reached 24 weeks of treatment.

The primary study endpoint was the time to first Clinical Events Committee (CEC) confirmed disease

progression up to 7 days after the last dose of study treatment. Secondary and exploratory endpoints

included safety and tolerability, change in 6MWD, WHO FC and in N-terminal prohormone of brain

natriuretic peptide (NT-proBNP) data, echocardiography, physical activity, and quality of life

measurements.

Overall, median treatment duration was 50 weeks and approximately 50% of patients reached

12 months of treatment. The majority of patients had idiopathic PAH (55.8%), were on background

combination therapy (74.6%) and were WHO FC II (76.8%). The mean age was 11.8 years (range 3–

18 years).

CEC-confirmed disease progression events were reported in 16 (23.2%) patients in the selexipag

group and 11 (15.9%) in the placebo group.

The nature of adverse events reported was consistent with the known safety profile of selexipag

(predominantly characterised by prostacyclin-like associated adverse reactions; see section 4.8) and

with the expected events in a PAH patient population including adverse events associated with PAH

disease progression. During the titration period, the adverse reaction vomiting was reported with a

higher frequency (19 [27.5%] in the selexipag group and 5 [7.2%] in the placebo group) as compared

to adults (see section 4.8). PAH disease progression was the most frequently reported serious adverse

event in 8 (11.6%) patients in the selexipag group compared to 4 (5.8%) in the placebo group. The

total number of deaths of all causes was 7 (10.1%) in the selexipag group and 5 (7.2%) in the placebo

group, of which 5 (7.2%) and 3 (4.3%) occurred during treatment on selexipag and placebo,

respectively. All deaths, except for one, were associated with PAH.

5.2 Pharmacokinetic properties

The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy

subjects. The pharmacokinetics of selexipag and the active metabolite, both after single-and

multiple-dose administration, were dose-proportional up to a single dose of 800 micrograms and

multiple doses of up to 1 800 micrograms twice daily. After multiple-dose administration, steady state

conditions of selexipag and the active metabolite were reached within 3 days. No accumulation in

plasma, either of parent compound or active metabolite, occurred after multiple-dose administration.

In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval) at

steady state was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject

variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively.

Exposure to selexipag and the active metabolite at steady state in PAH patients and healthy subjects

was similar. The pharmacokinetics of selexipag and the active metabolite in PAH patients were not

influenced by the severity of the disease and did not change with time.

Absorption

Selexipag is rapidly absorbed and is hydrolysed by carboxylesterases to its active metabolite.

Maximum observed plasma concentrations of selexipag and its active metabolite after oral

administration are reached within 1–3 h and 3–4 h, respectively.

The absolute bioavailability of selexipag in humans is approximately 49%. This is most probably due

to a first-pass effect of selexipag, as plasma concentrations of the active metabolite are similar after

the same oral and intravenous dose administration.

In the presence of food, the exposure to selexipag after a single dose of 400 micrograms was increased

by 10% in Caucasian subjects and decreased by 15% in Japanese subjects, whereas exposure to the

active metabolite was decreased by 27% (Caucasian subjects) and 12% (Japanese subjects). More

subjects reported adverse events after administration in the fasted than in the fed state.

Distribution

Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total

and to the same extent to albumin and alpha1-acid glycoprotein). The volume of distribution of

selexipag at steady state is 11.7 L.

Biotransformation

Selexipag is hydrolysed to its active metabolite in the liver and in the intestine by carboxylesterases.

Oxidative metabolism catalysed mainly by CYP2C8 and to a smaller extent by CYP3A4 leads to the

formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the

glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating

metabolites in human plasma exceed 3% of the total drug-related material. Both in healthy subjects

and PAH patients, after oral administration, exposure at steady state to the active metabolite is

approximately 3-to 4-fold higher than to the parent compound.

Elimination

Elimination of selexipag is predominantly via metabolism with a mean terminal half-life of 0.8–2.5 h.

The active metabolite has a half-life of 6.2–13.5 h. The total body clearance of selexipag is 17.9 L/h.

Excretion in healthy subjects was complete 5 days after administration and occurred primarily via

faeces (accounting for 93% of the administered dose) compared to 12% in urine.

Special populations

No clinically relevant effects of sex, race, age, or body weight on the pharmacokinetics of selexipag

and its active metabolite have been observed in healthy subjects or PAH patients.

Paediatric population

The pharmacokinetics of selexipag in paediatric patients aged ≥2 to < 18 years with PAH was studied

in the open-label, single-arm, phase 2 study (AC-065A203 [N =62]) and in SALTO [N =36] [see

section 5.1]).

Paediatric patients were administered selexipag at a starting dose of 100 micrograms twice daily (body

weight ≥9 kg and < 25 kg), 150 micrograms twice daily (body weight ≥25 kg and < 50 kg) and

200 micrograms twice daily (body weight ≥ 50 kg). The dose was up-titrated to the highest

individually tolerated dose up to a maximum of 800 micrograms twice daily (body weight ≥ 9 kg and

< 25 kg), 1 200 micrograms twice daily (body weight ≥ 25 kg and < 50 kg), and 1 600 micrograms

twice daily (body weight ≥ 50 kg). The applied body weight adjusted dosing regimen resulted in a

combined exposure of selexipag and its active metabolite comparable to that observed in adult

patients.

Renal impairment

A 1.4-to 1.7-fold increase in exposure (maximum plasma concentration and area under the plasma

concentration-time curve) to selexipag and its active metabolite was observed in subjects with severe

renal impairment (eGFR < 30 mL/min/1.73 m2).

Hepatic impairment

In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment,

exposure to selexipag was 2-and 4-fold higher, respectively, when compared to healthy subjects.

Exposure to the active metabolite remained almost unchanged in subjects with mild hepatic

impairment and was doubled in subjects with moderate hepatic impairment. Only two subjects with

severe (Child-Pugh class C) hepatic impairment were dosed with selexipag. Exposure to selexipag and

its active metabolite in these two subjects was similar to that in subjects with moderate (Child-Pugh

class B) hepatic impairment.

Based on modelling and simulation data from a study in subjects with hepatic impairment, the

exposure to selexipag at steady state in subjects with moderate hepatic impairment (Child-Pugh

class B) after a once-daily regimen is predicted to be approximately 2-fold higher than that in healthy

subjects during a twice-daily regimen. The exposure to the active metabolite at steady state in these

patients during a once-daily regimen is predicted to be similar to that in healthy subjects during a

twice-daily regimen. Subjects with severe hepatic impairment (Child-Pugh class C) showed similar

predicted exposure at steady state as subjects with moderate hepatic impairment during a once-daily

regimen.

5.3 Preclinical safety data

In the repeated-dose toxicity studies in rodents, strong blood pressure decrease as a result of

exaggerated pharmacology induced transient clinical signs and reduced food consumption and

body-weight gain. In adult and juvenile dogs, intestine and bone / bone marrow were identified as the

main target organs after treatment with selexipag. A delay in the closure of the femoral and/or tibial

epiphyseal growth plate was observed in juvenile dogs. A no-observed-adverse-effect level was not

established. In juvenile dogs, intussusception due to prostacyclin-related effects on intestinal motility

was observed sporadically. Safety margins adapted for IP receptor potency for the active metabolite

were 2-fold (based on total exposure) in relation to human therapeutic exposure. The finding did not

occur in mouse or rat toxicity studies. Because of the species-specific sensitivity of dogs to develop

intussusception, this finding is considered not relevant for adult humans.

Increased bone ossification and related changes in the bone marrow in dog studies are considered to be

due to the activation of EP4receptors in dogs. As human EP4receptors are not activated by selexipag

or its active metabolite, this effect is species-specific and, therefore, not relevant to humans.

Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted

genotoxicity studies.

In the 2-year carcinogenicity studies, selexipag caused an increased incidence of thyroid adenomas in

mice and Leydig cell adenomas in rats. The mechanisms are rodent-specific. Tortuosity of retinal

arterioles was noted after 2 years of treatment only in rats. Mechanistically, the effect is considered to

be induced by life-long vasodilation and subsequent changes in ocular haemodynamics. Additional

histopathological findings of selexipag were observed only at exposures sufficiently in excess of the

maximum human exposure, indicating little relevance to humans.

In a fertility study performed in rats, a prolongation of oestrus cycles resulting in increases in days

until copulation was observed at exposures 173-fold above therapeutic exposures (based on total

exposures), the no-observed-effect level being 30-fold above therapeutic exposures. Otherwise,

fertility parameters were not affected.

Selexipag was not teratogenic in rats and rabbits (exposure margins above therapeutic exposure of

13-fold for selexipag and 43-fold for the active metabolite, based on total exposure). Safety margins

for potential IP receptor-related effects on reproduction were 20 for fertility and 5 and 1 (based on free

exposure) for embryo-foetal development in rats and rabbits, respectively, when adapted for

differences in receptor potency. In the rat pre-/post-natal development study, selexipag induced no

effects on maternal and pup reproductive function.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Mannitol (E421)

Maize starch

Low-substituted hydroxypropylcellulose

Hydroxypropylcellulose

Magnesium stearate

Film coating

Uptravi 100 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide black (E172)

Carnauba wax

Talc

Uptravi 200 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Carnauba wax

Uptravi 400 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide red (E172)

Carnauba wax

Uptravi 600 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide black (E172)

Carnauba wax

Uptravi 800 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide black (E172)

Carnauba wax

Uptravi 1 000 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Carnauba wax

Uptravi 1 200 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide black (E172)

Iron oxide red (E172)

Carnauba wax

Uptravi 1 400 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Carnauba wax

Uptravi 1 600 microgram film-coated tablet

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide black (E172)

Iron oxide red (E172)

Iron oxide yellow (E172)

Carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister: 4 years.

Unopened bottle: 18 months.After the first opening of the bottle: 3 months or until the expiry date

(whichever occurs first).

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Uptravi 100 microgram film-coated tablets

High density polyethylene (HDPE) bottle with twist-off child-resistant closure,containing 1 g silica

desiccant capsule in the cap, and a heat seal liner.

Cartons of 60 film-coated tablets (bottles).

Cartons of 140 film-coated tablets (titration pack, bottles).

Uptravi 200 microgram film-coated tablets

Polyamide / aluminium / HDPE / PE with an embedded desiccant agent / HDPE blister sealed with an

aluminium foil.

Each blister strip contains 10 film-coated tablets.

Cartons of 10 or 60 film-coated tablets (1 or 6 blister strips).

Cartons of 60 or 140 film-coated tablets (titration packs, 6 or 14 blister strips).

Uptravi 400 microgram, 600 microgram, 800 microgram, 1 000 microgram, 1 200 microgram,

1 400 microgram, and 1 600 microgram film-coated tablets

Polyamide / aluminium / HDPE / PE with an embedded desiccant agent / HDPE blister sealed with an

aluminium foil.

Each blister strip contains 10 film-coated tablets

Cartons of 60 film-coated tablets (6 blister strips).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1083/001

EU/1/15/1083/002

EU/1/15/1083/003

EU/1/15/1083/004

EU/1/15/1083/005

EU/1/15/1083/006

EU/1/15/1083/007

EU/1/15/1083/008

EU/1/15/1083/009

EU/1/15/1083/010

EU/1/15/1083/011

EU/1/15/1083/012

EU/1/15/1083/013

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 May 2016

Date of latest renewal: 14 December 2020

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH

RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL

PRODUCT

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Janssen Pharmaceutica NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product

Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of

Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC

and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

Risk management plan (RMP)

The marketing authorisation holder (MAH)shall perform the required pharmacovigilance

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the

marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

At the request of the European Medicines Agency;

Whenever the risk management system is modified, especially as the result of new

information being received that may lead to a significant change to the benefit/risk profile or

as the result of an important (pharmacovigilance or risk minimisation) milestone being

reached.

Additional risk minimisation measures

Prior to the launch of Uptravi in each Member State, the MAH must agree on the content and format

of the Controlled Access System with the National Competent Authority.

The Controlled Access System is aimed to facilitate the identification of prescribers, to approach them

with the appropriate information on the safe and effective use of Uptravi, and to provide them with

risk minimisation tools, especially regarding the potential risk of medication error. The Controlled

Access System should include three key principles that will be incorporated within each system in all

Member States. These are:

The identification and maintenance of a list of all Uptravi prescribers;

The distribution of kits to all identified prescribers to minimise the risks of medication error in

particular;

Tracking of the receipt of the kits by prescribers.

The MAH shall ensure that in each Member State where Uptravi is marketed, all healthcare

professionals who are expected to prescribe and/or dispense Uptravi are provided with a Prescriber Kit

containing the following:

The Summary of Product Characteristics for Uptravi;

Cover letter to the healthcare professional;

Healthcare professional A4 laminated titration guide(s);

Patient titration guide(s);

Patient Leaflet.

The cover letter to the healthcare professional should explain that the purpose of the educational

materials is to reduce the risk of medication error due to the availability of multiple tablets and dose

strengths, and it should provide a list of the contents of the Prescriber Kit.

The healthcare professional A4 laminated titration guidesfor selexipag starting doses of

100 micrograms and 200 micrograms are intended to reduce the risk of medication error due to the

titration phase at treatment initiation with Uptravi and it should contain the following key elements:

The dosing and titration concept;

The move to the maintenance dose (titration phase);

Expectations and management of adverse reactions during the titration phase;

Encouragement and guidance for healthcare professionals to communicate clearly with the

patient during their first visit, as well as to take responsibility to contact the patient during the

titration phase, facilitating communication between healthcare professional and the patient

(need for contact and to schedule telephone calls).

Patient titration guides for selexipag starting doses of 100 micrograms and 200 micrograms are

available. The patient titration guide to be used by the healthcare professionals during discussions with

the patient should contain the following key elements:

Lay language version of the healthcare professional A4 laminated titration guide;

Diary to facilitate Uptravi use and serve as a reminder for the patients (e.g., to contact her/his

doctor), and a place to record intake of tablets;

Information about the safe and effective use of Uptravi in lay language.

The patient titration guide corresponding to the patient's selexipag starting dose of 100 micrograms or

200 micrograms along with the Patient Information Leaflet should be given to the patient after the

demonstration. Patients will receive a titration guide and Patient Leaflet in their titration packs of

Uptravi.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON -TITRATION PACK

1. NAME OF THE MEDICINAL PRODUCT

Uptravi 100 microgram film-coated tablets

selexipag

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 100 micrograms of selexipag.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet

Titration pack

140 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not split or crush.

Read the package leaflet and titration guide before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Use within 3 months after the first opening.

Open date:

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1083/013

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Uptravi 100 microgram

17. UNIQUE IDENTIFIER –2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER -HUMAN READABLE DATA

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Uptravi 100 microgram film-coated tablets

selexipag

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 100 micrograms of selexipag.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet

60 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not split or crush.

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Use within 3 months after the first opening.

Open date:

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1083/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Uptravi 100 microgram

17. UNIQUE IDENTIFIER –2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER -HUMAN READABLE DATA

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

Uptravi 100 microgram film-coated tablets

selexipag

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 100 micrograms of selexipag.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet

60 film-coated tablets

140 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not split or crush.

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Use within 3 months after the first opening.

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1083/012

EU/1/15/1083/013

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER –2D BARCODE

18. UNIQUE IDENTIFIER -HUMAN READABLE DATA

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON -TITRATION PACK

1. NAME OF THE MEDICINAL PRODUCT

Uptravi 200 microgram film-coated tablets

selexipag

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 200 micrograms of selexipag.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet

Titration pack

60 film-coated tablets

140 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not split or crush.

Read the package leaflet and titration guide before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1083/003

EU/1/15/1083/011

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Uptravi 200 microgram